Assessment and grading of mucosal inflammation in colonic diverticular disease.
The aim of this study was to assess and grade the mucosal inflammatory infiltrate in different degrees of diverticular disease (DD) and to compare them with healthy matched controls. Mucosal inflammation in colonic DD has never been investigated. In particular, it is unknown whether inflammation may be found in every degree of DD. Thirty consecutive patients with a new endoscopic diagnosis of DD (10 with asymptomatic diverticulosis, 10 with symptomatic uncomplicated DD, and 10 with acute uncomplicated diverticulitis) and 10 healthy controls were studied. A neutrophilic inflammatory infiltrate was found only in acute uncomplicated diverticulitis (overall score, 26). The mean lymphocytic cell density was significantly higher in symptomatic DD (median lymphocytic density, 7) and acute uncomplicated diverticulitis (median lymphocytic density, 11). Subdividing the patients according to different degrees of DD, we found higher lymphocytic cell density even in asymptomatic diverticulosis (median lymphocytic density, 6.5) than healthy controls (median lymphocytic density, 4; P<0.02). We found an increased inflammatory infiltrate in DD according to the degree of the disease and higher than healthy controls. Moreover, also asymptomatic diverticulosis shows higher inflammatory cell density than controls.


Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs.
To estimate the relative risk for peptic ulcer disease that is associated with the use of oral corticosteroids. A nested case-control study. Tennessee Medicaid program. The case patients (n = 1415) were hospitalized between 1984 and 1986 for gastric or duodenal ulcer or for upper gastrointestinal hemorrhage of unknown cause. The controls (n = 7063) were randomly selected from Medicaid enrollees not meeting the study criteria for inclusion as case patients. The estimated relative risk for the development of peptic ulcer disease among current users of oral corticosteroids was 2.0 (95% CI, 1.3 to 3.0). However, the risk was increased only in those who concurrently received nonsteroidal anti-inflammatory drugs (NSAIDs); these persons had an estimated relative risk associated with current corticosteroid use of 4.4 (CI, 2.0 to 9.7). In contrast, the estimated relative risk for those corticosteroid users not receiving NSAIDs was 1.1 (CI, 0.5 to 2.1). Persons concurrently receiving corticosteroids and NSAIDs had a risk for peptic ulcer disease that was 15 times greater than that of nonusers of either drug. Discrepant findings among earlier studies regarding steroids and the risk for peptic ulcer disease could in part be due to differences in the use of NSAIDs among study participants. The high risk for peptic ulcer disease associated with combined use of NSAIDs and corticosteroids indicates the need to prescribe this drug combination cautiously.


Phospho.ELM: a database of experimentally verified phosphorylation sites in eukaryotic proteins.
Post-translational phosphorylation is one of the most common protein modifications. Phosphoserine, threonine and tyrosine residues play critical roles in the regulation of many cellular processes. The fast growing number of research reports on protein phosphorylation points to a general need for an accurate database dedicated to phosphorylation to provide easily retrievable information on phosphoproteins. Phospho.ELM http://phospho.elm.eu.org is a new resource containing experimentally verified phosphorylation sites manually curated from the literature and is developed as part of the ELM (Eukaryotic Linear Motif) resource. Phospho.ELM constitutes the largest searchable collection of phosphorylation sites available to the research community. The Phospho.ELM entries store information about substrate proteins with the exact positions of residues known to be phosphorylated by cellular kinases. Additional annotation includes literature references, subcellular compartment, tissue distribution, and information about the signaling pathways involved as well as links to the molecular interaction database MINT. Phospho.ELM version 2.0 contains 1703 phosphorylation site instances for 556 phosphorylated proteins. Phospho.ELM will be a valuable tool both for molecular biologists working on protein phosphorylation sites and for bioinformaticians developing computational predictions on the specificity of phosphorylation reactions.


SU-E-T-124: A Modified Winston Lutz Test Enabling Beam to Laser Angle Measurements.
To present a modified Winston-Lutz-Test procedure able to measure beam and laser angles. Room lasers have not only to indicate the isocenter spot but should also be aligned to the central beam axis. Therefore a modified WL test, based on a cube phantom made of low density foam material was developed. The classical steel sphere in the center is surrounded by 8 additional smaller spheres located near the cube corners. Surface markers on the cube indicate the position of the spheres and are used for easy setup to the lasers. Measurements are made with a field size covering all spheres in the well known way, ideally with a gantry mounted EPID. Result is an image of in total 9 spheres that is influenced by the distances and incoming beam directions. An automated template based detection algorithm then searches the image for the spheres as well as for the outside field boundaries. Knowing the phantom geometry, it is now easy to calculate the following parameters: Position of center sphere and laser to central axis of the beam, beam angle to the orientation of the phantom and the distance of the cube to the radiation source. Calculation result s then can be used to correct the phantom position and orientation. A transfer device equipped with a finder sight then allows to set the lasers. Test measurements were taken at a Siemens Artiste. Here the detection accuracy for angles and positions was tested. For smaller angles the automated detection works quite well within an accuracy of around 0.1° (max error 0.2°). Position detection was below 1/10mm and showed clearly the effects of Gantry and collimator sag. This method detects both, positions and angles of laser and beam, enabling a higher precision laser setup.


Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.


Cross-Disciplinary Biomarkers Research: Lessons Learned by the CKD Biomarkers Consortium.
Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays.


Adaptive fractionation therapy: I. Basic concept and strategy.
Radiotherapy is fractionized to increase the therapeutic ratio. Fractionation in conventional treatment is determined as part of the prescription, and a fixed fraction size is used for the whole course of treatment. Due to patients' day-to-day variations on the relative distance between the tumor and the organs at risk (OAR), a better therapeutic ratio may be attained by using an adaptive fraction size. Intuitively, we want to use a larger fraction size when OAR and the tumor are far apart and a smaller fraction size when OAR and the tumor are close to each other. The concept and strategies of adaptive fractionation therapy (AFT) are introduced in this paper. AFT is an on-line adaptive technique that utilizes the variations of internal structures to get optimal OAR sparing. Changes of internal structures are classified as different configurations according to their feasibility to the radiation delivery. A priori knowledge is used to describe the probability distribution of these configurations. On-line processes include identifying the configuration via daily image guidance and optimizing the current fraction size. The optimization is modeled as a dynamic linear programming problem so that at the end of the treatment course, the tumor receives the same planned dose while OAR receives less dose than the regular fractionation delivery. Extensive simulations, which include thousands of treatment courses with each course consisting of 40 fractions, are used to test the efficiency and robustness of the presented technique. The gains of OAR sparing depend on the variations on configurations and the bounds of the fraction size. The larger the variations and the looser the bounds are, the larger the gains will be. Compared to the conventional fractionation technique with 2 Gy/fraction in 40 fractions, for a 20% variation on tumor-OAR configurations and [1 Gy, 3 Gy] fraction size bounds, the cumulative OAR dose with adaptive fractionation is 3-8 Gy, or 7-20% less than that of the regular fractionation, while maintaining the same cumulative tumor dose as prescribed.


Self-enhanced multicolor electrochemiluminescence by competitive electron-transfer processes.
Controlling electrochemiluminescence (ECL) color(s) is crucial for many applications ranging from multiplexed bioassays to ECL microscopy. This can only be achieved through the fundamental understanding of high-energy electron-transfer processes in complex and competitive reaction schemes. Recently, this field has generated huge interest, but the effective implementation of multicolor ECL is constrained by the limited number of ECL-active organometallic dyes. Herein, the first self-enhanced organic ECL dye, a chiral red-emitting cationic diaza [4]helicene connected to a dimethylamino moiety by a short linker, is reported. This molecular system integrates bifunctional ECL features (i.e. luminophore and coreactant) and each function may be operated either separately or simultaneously. This unique level of control is enabled by integrating but decoupling both molecular functions in a single molecule. Through this dual molecular reactivity, concomitant multicolor ECL emission from red to blue with tunable intensity is readily obtained in aqueous media. This is done through competitive electron-transfer processes between the helicene and a ruthenium or iridium dye. The reported approach provides a general methodology to extend to other coreactant/luminophore systems, opening enticing perspectives for spectrally distinct detection of several analytes, and original analytical and imaging strategies.


Arabidopsis SDG8 Potentiates the Sustainable Transcriptional Induction of the Pathogenesis-Related Genes PR1 and PR2 During Plant Defense Response.
Post-translational covalent modifications of histones play important roles in modulating chromatin structure and are involved in the control of multiple developmental processes in plants. Here we provide insight into the contribution of the histone lysine methyltransferase SET DOMAIN GROUP 8 (SDG8), implicated in histone H3 lysine 36 trimethylation (H3K36me3), in connection with RNA polymerase II (RNAPII) to enhance Arabidopsis immunity. We showed that even if the sdg8-1 loss-of-function mutant, defective in H3K36 methylation, displayed a higher sensitivity to different strains of the bacterial pathogen Pseudomonas syringae, effector-triggered immunity (ETI) still operated, but less efficiently than in the wild-type (WT) plants. In sdg8-1, the level of the plant defense hormone salicylic acid (SA) was abnormally high under resting conditions and was accumulated similarly to WT at the early stage of pathogen infection but quickly dropped down at later stages. Concomitantly, the transcription of several defense-related genes along the SA signaling pathway was inefficiently induced in the mutant. Remarkably, albeit the defense genes PATHOGENESIS-RELATED1 (PR1) and PR2 have retained responsiveness to exogenous SA, their inductions fade more rapidly in sdg8-1 than in WT. At chromatin, while global levels of histone methylations were found to be stable, local increases of H3K4 and H3K36 methylations as well as RNAPII loading were observed at some defense genes following SA-treatments in WT. In sdg8-1, the H3K36me3 increase was largely attenuated and also the increases of H3K4me3 and RNAPII were frequently compromised. Lastly, we demonstrated that SDG8 could physically interact with the RNAPII C-terminal Domain, providing a possible link between RNAPII loading and H3K36me3 deposition. Collectively, our results indicate that SDG8, through its histone methyltransferase activity and its physical coupling with RNAPII, participates in the strong transcriptional induction of some defense-related genes, in particular PR1 and PR2, to potentiate sustainable immunity during plant defense response to bacterial pathogen.


MAP kinase does not inactivate, but rather prevents the cyclin degradation pathway from being turned on in Xenopus egg extracts.
Unfertilized frog eggs arrest at the second meiotic metaphase, due to cytostatic activity of the c-mos proto-oncogene (CSF). MAP kinase has been proposed to mediate CSF activity in suppressing cyclin degradation. Using an in vitro assay to generate CSF activity, and recombinant CL 100 phosphatase to inactivate MAP kinase, we confirm that the c-mos proto-oncogene blocks cyclin degradation through MAP kinase activation. We further show that for MAP kinase to suppress cyclin degradation, it must be activated before cyclin B-cdc2 kinase has effectively promoted cyclin degradation. Thus MAP kinase does not inactivate, but rather prevents the cyclin degradation pathway from being turned on. Using a constitutively active mutant of Ca2+/calmodulin dependent protein kinase II, which mediates the effects of Ca2+ at fertilization, we further show that the kinase can activate cyclin degradation in the presence of both MPF and the c-mos proto-oncogene without inactivating MAP kinase.


Are the recommendations being met in the general practice year of vocational training? Trainees' views in the West Midlands region.
Vocational trainees in the West Midlands who were in their general practice year were sent a postal questionnaire to find out whether there were important differences between the criteria for training of the 1986 West Midland postgraduate education committee (based on national recommendations) and the perceptions of the trainees of their current trainers and practices. The response rate was 86.2% (75 out of 87). Sixty four per cent (48) of trainees reported that they received on average less than the recommended minimum of three hours of teaching time a week. They felt that experience was inadequate in paediatric surveillance (62.7%) and preventive medical care (37.3%). Most trainers gave topic teaching (90.7%), and few used role play (5%). Most of the trainees (52%) had not signed a contract, a third did not get help with recommended allowances, and 37% thought that their progress had not been reviewed. Several trainees commented on the excellence of their training practices, and most of the practices appeared to be keeping to the spirit of the recommendations. There are, however, discrepancies between what some trainees feel they receive and what is recommended.


Pyrrolysine encoded by UAG in Archaea: charging of a UAG-decoding specialized tRNA.
Pyrrolysine is a lysine derivative encoded by the UAG codon in methylamine methyltransferase genes of Methanosarcina barkeri. Near a methyltransferase gene cluster is the pylT gene, which encodes an unusual transfer RNA (tRNA) with a CUA anticodon. The adjacent pylS gene encodes a class II aminoacyl-tRNA synthetase that charges the pylT-derived tRNA with lysine but is not closely related to known lysyl-tRNA synthetases. Homologs of pylS and pylT are found in a Gram-positive bacterium. Charging a tRNA(CUA) with lysine is a likely first step in translating UAG amber codons as pyrrolysine in certain methanogens. Our results indicate that pyrrolysine is the 22nd genetically encoded natural amino acid.


BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma.
We characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2 mutations (20% BRCA1 and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1 (group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P=0.0008). Among high-grade serous carcinomas, there were no differences between groups 1-3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P=0.034, 0.027). TP53 expression differed between groups (P<0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (P<0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.


Opposite selection on behavioural types by active and passive fishing gears in a simulated guppy Poecilia reticulata fishery.
This study assessed whether fishing gear was selective on behavioural traits, such as boldness and activity, and how this was related with a productivity trait, growth. Female guppies Poecilia reticulata were screened for their behaviour on the shy-bold axis and activity, and then tested whether they were captured differently by passive and active fishing gear, here represented by a trap and a trawl. Both gears were selective on boldness; bold individuals were caught faster by the trap, but escaped the trawl more often. Boldness and gear vulnerability showed weak correlations with activity and growth. The results draw attention to the importance of the behavioural dimension of fishing: selective fishing on behavioural traits will change the trait composition of the population, and might eventually affect resilience and fishery productivity.


Acceptance of drinking and driving and alcohol-involved driving crashes in California.
Alcohol-impaired driving accounts for substantial proportion of traffic-related fatalities in the U.S. Risk perceptions for drinking and driving have been associated with various measures of drinking and driving behavior. In an effort to understand how to intervene and to better understand how risk perceptions may be shaped, this study explored whether an objective environmental-level measure (proportion of alcohol-involved driving crashes in one's residential city) were related to individual-level perceptions and behavior. Using data from a 2012 cross-sectional roadside survey of 1147 weekend nighttime drivers in California, individual-level self-reported acceptance of drinking and driving and past-year drinking and driving were merged with traffic crash data using respondent ZIP codes. Population average logistic regression modeling was conducted for the odds of acceptance of drinking and driving and self-reported, past-year drinking and driving. A non-linear relationship between city-level alcohol-involved traffic crashes and individual-level acceptance of drinking and driving was found. Acceptance of drinking and driving did not mediate the relationship between the proportion of alcohol-involved traffic crashes and self-reported drinking and driving behavior. However, it was directly related to behavior among those most likely to drink outside the home. The present study surveys a particularly relevant population and is one of few drinking and driving studies to evaluate the relationship between an objective environmental-level crash risk measure and individual-level risk perceptions. In communities with both low and high proportions of alcohol-involved traffic crashes there was low acceptance of drinking and driving. This may mean that in communities with low proportions of crashes, citizens have less permissive norms around drinking and driving, whereas in communities with a high proportion of crashes, the incidence of these crashes may serve as an environmental cue which informs drinking and driving perceptions. Perceptual information on traffic safety can be used to identify places where people may be at greater risk for drinking and driving. Community-level traffic fatalities may be a salient cue for tailoring risk communication.


Short monolithic columns as stationary phases for biochromatography.
Monolithic supports represent a novel type of stationary phases for liquid and gas chromatography, for capillary electrochromatography, and as supports for bioconversion and solid phase synthesis. As opposed to individual particles packed into chromatographic columns, monolithic supports are cast as continuous homogeneous phases. They represent an approach that provides high rates of mass transfer at lower pressure drops as well as high efficiencies even at elevated flow rates. Therefore, much faster separations are possible and the productivity of chromatographic processes can be increased by at least one order of magnitude as compared to traditional chromatographic columns packed with porous particles. Besides the speed, the nature of the pores allows easy access even in the case of large molecules, which make monolithic supports a method of choice for the separation of nanoparticles like pDNA and viruses. Finally, for the optimal purification of larger biomolecules, the chromatographic column needs to be short. This enhances the speed of the separation process and reduces backpressure, unspecific binding, product degradation and minor changes in the structure of the biomolecule, without sacrificing resolution. Short Monolithic Columns (SMC) were engineered to combine both features and have the potential of becoming the method of choice for the purification of larger biomolecules and nanopartides on the semi-preparative scale.


Measuring adherence to antihypertensive medication using an objective test in older adults attending primary care: cross-sectional study.
Analysis of urine samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has previously revealed high rates of non-adherence to antihypertensive medication. It is unclear whether these rates represent those in the general population. This study aimed to investigate whether it is feasible to collect urine samples in a primary care setting and analyse them using LC-MS/MS to detect non-adherence to antihypertensive medication. This study used a prospective, observational cohort design. Consecutive patients were recruited opportunistically from five general practices in UK primary care. They were aged ≥65 years with hypertension and had at least one antihypertensive prescription. Participants were asked to provide a urine sample for analysis of medication adherence. Samples were sent to a laboratory via post and analysed using LC-MS/MS. Predictors of adherence to medication were explored with multivariable logistic regression. Of 349 consecutive patients approached for the study, 214 (61.3%) gave informed consent and 191 (54.7%) provided a valid urine sample for analysis. Participants were aged 76.2 ± 6.6 years and taking a median of 2 antihypertensive medications (IQR 1-3). A total of 27/191 participants (14.2%) reported not taking all of their medications on the day of urine sample collection. However, LC-MS/MS analysis of samples revealed only 4/27 (9/191 in total; 4.7%) were non-adherent to some of their medications. Patients prescribed more antihypertensive medications were less likely to be adherent (OR 0.24, 95%CI 0.09-0.65). Biochemical testing for antihypertensive medication adherence is feasible in routine primary care, although non-adherence to medication is generally low, and therefore widespread testing is not indicated.


Excited-state intramolecular proton-transfer reaction demonstrating anti-Kasha behavior.
We report unusual photophysical properties observed on two newly designed 3-hydroxychromone derivatives exhibiting the excited-state intramolecular proton transfer (ESIPT) reaction. The efficiency of ESIPT reaction is greatly enhanced upon excitation with high energy quanta to S n (n > 1) levels in low-polarity solvents. Based on detailed analyses of excitation and emission spectra as well as time-resolved emission kinetics we derive that conditions, in which this phenomenon contradicting Kasha's rule is observed, are quite different from that for observation of anti-Kasha emission.


The effect of oral and parenteral vitamin D supplementation in the elderly: a prospective, double-blinded, randomized, placebo-controlled study.
Hypovitaminosis D in the elderly causes falls and fractures as a result of impaired neuromuscular functions and also may be a reason for nonspecific musculosceletal pain. The aim of this study is to investigate the benefits of a single dose per os or parenterally administrated vitamin D on increasing the quality of life and functional mobility and decreasing the pain in the elderly. The community-dwelling elderly subjects over 65 years age were included in the study. The subjects were given 300.000 IU Vitamin D via per os and parenteral route and assessed after 4 weeks. The serum creatinine, calcium, phosphorous, ALT, ALP, 24-h urine calcium excretion, PTH, and vitamin D levels, as well as VAS (visual analog scale) for pain assessment, functional mobility with TUG (timed up and go test) and quality of life with SF-36 before and after the treatment were evaluated. The serum vitamin D levels were measured by the RIA method. The subjects were divided into four groups each consisting of 30 subjects. The 1st group took i.m. vitamin D, the 2nd group took i.m. placebo, the 3rd group took p.o. vitamin D, and the 4th group took p.o. placebo. The mean age of all the participants was 70.1 ± 4.3 years. There was no difference in the age and gender between the groups (P > 0.05). After treatment, the PTH level of first group was decreased (P = 0.0001) and the vitamin D level increased (P = 0.0001) significantly. In the third group, the PTH level of first group was decreased (P = 0.0001) and the vitamin D level increased (P = 0.004) and the 24-h calcium excretion in urine (P = 0.015) increased significantly. When the pain, the functional mobility, and the quality of life were evaluated, in the first group, the TUG (P = 0.0001) and the VAS (P = 0.0001) decreased significantly, whereas the SF-36 subtitles: physical functioning (P = 0.0001), role physical (0.006), bodily pain (P = 0.0001), general health (P = 0.007), social functioning (P = 0.05), and mental health (P = 0.048) increased significantly. In group two, the VAS (P = 0.001) decreased, the role physical (P = 0.009), and role emotional (P = 0.034) increased significantly; In group three, the TUG (P = 0.0001) and the VAS (P = 0.002) decreased, whereas the physical function (P = 0.0001) and role physical (0.001) increased significantly; In group four, the VAS (P = 0.007) decreased significantly. The megadose vitamin D administration increases quality of life, decreases pain, and improves functional mobility via po or im route in the elderly.


Genetic variation in CD38 and breastfeeding experience interact to impact infants' attention to social eye cues.
Attending to emotional information conveyed by the eyes is an important social skill in humans. The current study examined this skill in early development by measuring attention to eyes while viewing emotional faces in 7-mo-old infants. In particular, we investigated individual differences in infant attention to eyes in the context of genetic variation (CD38 rs3796863 polymorphism) and experiential variation (exclusive breastfeeding duration) related to the oxytocin system. Our results revealed that, whereas infants at this age show a robust fear bias (increased attention to fearful eyes), their attention to angry and happy eyes varies as a function of exclusive breastfeeding experience and genetic variation in CD38. Specifically, extended exclusive breastfeeding duration selectively enhanced looking preference to happy eyes and decreased looking to angry eyes. Importantly, however, this interaction was impacted by CD38 variation, such that only the looking preferences of infants homozygous for the C allele of rs3796863 were affected by breastfeeding experience. This genotype has been associated with reduced release of oxytocin and higher rates of autism. In contrast, infants with the CA/AA genotype showed similar looking preferences regardless of breastfeeding exposure. Thus, differences in the sensitivity to emotional eyes may be linked to an interaction between the endogenous (CD38) and exogenous (breastfeeding) availability of oxytocin. These findings underline the importance of maternal care and the oxytocin system in contributing to the early development of responding to social eye cues.


Effectiveness of a Mindfulness-Based Childbirth Education pilot study on maternal self-efficacy and fear of childbirth.
This pilot study tested the feasibility and effectiveness of using Mindfulness-Based Childbirth Education (MBCE), a novel integration of mindfulness meditation and skills-based childbirth education, for mental health promotion with pregnant women. The MBCE protocol aimed to reduce fear of birth, anxiety, and stress and improve maternal self-efficacy. This pilot study also aimed to determine the acceptability and feasibility of the MBCE protocol. A single-arm pilot study of the MBCE intervention using a repeated-measures design was used to analyze data before and after the MBCE intervention to determine change trends with key outcome variables: mindfulness; depression, anxiety, and stress; childbirth self-efficacy; and fear of childbirth. Pregnant women (18-28 weeks' gestation) and their support companions attended weekly MBCE group sessions over 8 weeks in an Australian community setting. Of the 18 women who began and completed the intervention, missing data allowed for complete data from 12 participants to be analyzed. Statistically significant improvements and large effect sizes were observed for childbirth self-efficacy and fear of childbirth. Improvements in depression, mindfulness, and birth outcome expectations were underpowered. At postnatal follow-up significant improvements were found in anxiety, whereas improvements in mindfulness, stress, and fear of birth were significant at a less conservative alpha level. This pilot study demonstrated that a blended mindfulness and skills-based childbirth education intervention was acceptable to women and was associated with improvements in women's sense of control and confidence in giving birth. Previous findings that low self-efficacy and high childbirth fear are linked to greater labor pain, stress reactivity, and trauma suggest the observed improvements in these variables have important implications for improving maternal mental health and associated child health outcomes. Ways in which these outcomes can be achieved through improved childbirth education are discussed.


Bracing in pediatric patients with pectus carinatum is effective and improves quality of life.
The purpose of this study was to examine the effectiveness and patient satisfaction with bracing for pectus carinatum (PC). Twenty-five PC patients were treated between August 2007 and October 2011. Most patients were male (21/25,84%) with a mean age of 14.4 ± 2.0 yrs. A lightweight, patient controlled, external brace (Braceworks, Calgary, AB) was used. Monthly follow-up with anterior-posterior (AP) width measurements occurred until bracing was completed. Three quality of life (QOL) questionnaires were used: SF-36, SSQ, and PEEQ. Group 1 involved twenty patients who successfully completed bracing (12/25,56%) or who are still bracing (8/25,32%). Group 2 comprised five patients who failed bracing (2/25,8%) or who were noncompliant (3/25,12%). One patient who failed bracing underwent successful Ravitch repair. AP width decreased more in those with successful bracing (2.31 vs 0.64 cm, p=0.05). Questionnaires were completed by 19/25 (76%) patients. Pre-bracing, the SF-36, and PEEQ revealed that few patients were symptomatic, although most still avoided activities which showed their chest. The SSQ revealed that the majority of patients were very satisfied with their post-bracing appearance, experienced minimal discomfort while bracing, and would use the brace again. Self-esteem increased significantly after bracing (7.5 vs 8.7, p=0.01). Bracing in PC patients is very effective in a compliant patient with close follow-up. Surgical repair remains feasible if bracing fails.


Heterogeneous multireference alignment for images with application to 2-D classification in single particle reconstruction.
Motivated by the task of 2-D classification in single particle reconstruction by cryo-electron microscopy (cryo-EM), we consider the problem of heterogeneous multireference alignment of images. In this problem, the goal is to estimate a (typically small) set of target images from a (typically large) collection of observations. Each observation is a rotated, noisy version of one of the target images. For each individual observation, neither the rotation nor which target image has been rotated are known. As the noise level in cryo-EM data is high, clustering the observations and estimating individual rotations is challenging. We propose a framework to estimate the target images directly from the observations, completely bypassing the need to cluster or register the images. The framework consists of two steps. First, we estimate rotation-invariant features of the images, such as the bispectrum. These features can be estimated to any desired accuracy, at any noise level, provided sufficiently many observations are collected. Then, we estimate the images from the invariant features. Numerical experiments on synthetic cryo-EM datasets demonstrate the effectiveness of the method. Ultimately, we outline future developments required to apply this method to experimental data.


Stage-specific elevated expression of the genes for hepatocyte growth factor, keratinocyte growth factor, and their receptors during the morphogenesis and differentiation of rat stomach mucosa.
Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are two factors considered to be involved in the morphogenesis of several organs. To understand the role of HGF and KGF in the stomach development, we analyzed changes in the levels of expression of the genes for the two growth factors and their receptors in the fetal rat stomach by competitive RT-PCR. Resembling our previous results for HGF, the expression of the genes for KGF and its receptor was observed in the mesenchyme and epithelium of 16.5 day fetal stomach, respectively, indicating the possibility that KGF mediates the epithelial-mesenchymal interaction in the early stage of stomach development. The developmental profile of the expression of the genes for the two growth factors and their receptors were different, indicating a difference in their roles; the genes for HGF and c-met, the receptor for HGF, are expressed mainly during the morphogenetic period, while the genes for KGF and its receptor mainly after the morphogenetic period. Thus, it is probable that HGF controls the proliferation of epithelial cells during the morphogenetic process. The expression of the genes for KGF and its receptor is not correlated with epithelial proliferation during morphogenesis, but it does appear to be linked with epithelial differentiation. These results, together with the absence of significant mitogenic effect of KGF on the epithelial cells of the fetal rat glandular stomach in vitro, suggest a role for KGF as a differentiation factor. In addition, the expression profile of the genes for KGF and its receptor towards the end of fetal period appears to be closely correlated with that of mesenchymal cell proliferation, suggesting another role for the growth factor that is not regulated by the epithelial-mesenchymal interaction.


Assessing progress in reducing the at-risk population after 13 years of the global programme to eliminate lymphatic filariasis.
In 1997, the World Health Assembly adopted Resolution 50.29, committing to the elimination of lymphatic filariasis (LF) as a public health problem, subsequently targeted for 2020. The initial estimates were that 1.2 billion people were at-risk for LF infection globally. Now, 13 years after the Global Programme to Eliminate Lymphatic Filariasis (GPELF) began implementing mass drug administration (MDA) against LF in 2000-during which over 4.4 billion treatments have been distributed in 56 endemic countries-it is most appropriate to estimate the impact that the MDA has had on reducing the population at risk of LF. To assess GPELF progress in reducing the population at-risk for LF, we developed a model based on defining reductions in risk of infection among cohorts of treated populations following each round of MDA. The model estimates that the number of people currently at risk of infection decreased by 46% to 789 million through 2012. Important progress has been made in the global efforts to eliminate LF, but significant scale-up is required over the next 8 years to reach the 2020 elimination goal.


Is health insurance enough? A usual source of care may be more important to ensure a child receives preventive health counseling.
Despite the promise of expanded health insurance coverage for children in the United States, a usual source of care (USC) may have a bigger impact on a child's receipt of preventive health counseling. We examined the effects of insurance versus USC on receipt of education and counseling regarding prevention of childhood injuries and disease. We conducted secondary analyses of 2002-2006 data from a nationally-representative sample of child participants (≤17 years) in the Medical Expenditure Panel Survey (n = 49,947). Children with both insurance and a USC had the lowest rates of missed counseling, and children with neither one had the highest rates. Children with only insurance were more likely than those with only a USC to have never received preventive health counseling from a health care provider regarding healthy eating (aRR 1.21, 95% CI 1.12-1.31); regular exercise (aRR 1.06, 95% CI 1.01-1.12), use of car safety devices (aRR 1.10, 95% CI 1.03-1.17), use of bicycle helmets (aRR 1.11, 95% CI 1.05-1.18), and risks of second hand smoke exposure (aRR 1.12, 95% CI 1.04-1.20). A USC may play an equally or more important role than insurance in improving access to health education and counseling for children. To better meet preventive counseling needs of children, a robust primary care workforce and improved delivery of care in medical homes must accompany expansions in insurance coverage.


Effect of L-tryptophan supplementation on exercise performance.
The performance of strenuous physical exercise is associated with discomfort and pain, the tolerance for that being modulated by the activity of the endogenous opioid systems. As 5-hydroxy-tryptamine (5-HT) affects nociception through its effects on the enkephalin-endorphin system, we have analyzed the effects of a moderate supplementation with L-tryptophan, the immediate precursor of 5-HT, on endurance and sensation of effort. Twelve healthy sportsmen were subjected to a work load corresponding to 80% of their maximal oxygen uptake on two separate trials, after receiving a placebo and after receiving the same amount of L-tryptophan. The subjects ran on a treadmill until exhaustion. Total exercise time, perceived exertion rate, maximum heart rate, peak oxygen consumption, pulse recovery rate, and excess post-exercise oxygen consumption were determined during the two trials. The total exercise time was 49.4% greater after receiving L-tryptophan than after receiving the placebo. A lower rate of perceived exertion was exhibited by the group while on tryptophan although the differences from the control group were not statistically significant. No differences were observed in the other parameters between the two trials. The longer exercise time als well at the total work load performed could be due to an increased pain tolerance as a result of L-tryptophan ingestion.


Measuring sexual behaviour in the era of HIV/AIDS: the experience of Demographic and Health Surveys and similar enquiries.
To review the sexual behaviour data collected in the Demographic and Health Surveys (DHS) and other similar national surveys from the perspective of data quality. Two indicators of premarital and higher risk sexual behaviour were analysed for 31 surveys in 10 countries in sub-Saharan Africa and Latin America and the Caribbean. The analysis focused on the internal consistency of trends and gender differences in the reported indicators. The authors found fluctuating trends in premarital sex in sub-Saharan Africa but consistent increases in Latin America and the Caribbean. Changes in questionnaire design do not seem to contribute to these trends and there is evidence that the increase in premarital sex is genuine in Latin America. Trends in sex with non-spousal, non-cohabiting partners show large fluctuations and inconsistencies between surveys in some countries but not others. Men are consistently more likely to report non-marital sexual partners than women and unmarried women are less likely than unmarried men to report casual partners. Surveys are potentially a valuable source of information on sexual behaviour but there are sufficient grounds for concern to warrant considerable caution in the use of survey data to monitor trends in sexual behaviour. Survey findings must be evaluated carefully and interpreted in the context of other available information. These results caution against placing heavy emphasis on short term changes in sexual behaviour between individual surveys and highlight the need for attention to quality in data collection.


Contextualising merit and integrity within human research.
The first consideration of any Australian Human Research Ethics Committee should be to satisfy itself that the project before them is worth undertaking. If the project does not add to the body of knowledge, if it does not improve social welfare or individual wellbeing then the use of human participants, their tissue or their data must be questioned. Sometimes, however, committees are criticised for appearing to adopt the role of scientific review committees. The intent of this paper is to provide researchers with an understanding of the ethical importance of demonstrating the merit of their research project and to help them develop protocols that show ethics committees that adequate attention has been paid to this central tenet in dealing ethically with human research participants. Any person proposing human research must be prepared to show that it is worthwhile. This paper will clarify the relationship between research merit and integrity, research ethics and the responsibilities of human research ethics committees.


Do non-terminally ill adults want to discuss the end of life with their family physician? An explorative mixed-method study on patients' preferences and family physicians' views in Belgium.
Research about advance care planning (ACP) has often targeted those with serious illness and limited prognosis, thereby not addressing the preferences of healthy adults or adults with a stable condition. (i) To describe to what extent patients aged 50 and older who are relatively stable or in good health are thinking about the end of life (EOL) and willing to discuss this with their family physician (FP) and (ii) to explore whether patients and FPs indicate the same topics as triggers for ACP discussions in family practice. A cross-sectional study was conducted in a diverse sample of 289 patients aged ≥50 years in family practice in Flanders, Belgium. Subsequently, semi-structured interviews were conducted with patients (n = 5) and FPs (n = 5) to explore their preferences and views on ACP in family practice. The majority (69.8%) of patients had thought about the EOL and would appreciate it if their FP would initiate a conversation about this (75.9%). The qualitative interviews revealed that when thinking about the EOL, a number of themes captured the thoughts of people according to both patients and FPs: (i) becoming care dependent, (ii) physical and mental deterioration, (iii) dying alone and (iv) having paperwork in order. However, on the basis of patients' ideas and FPs' experiences in practice, a difference was noticed between them when it comes to identifying the themes as triggers for initiating ACP discussions. Although patients are willing to discuss the EOL with their FPs, patients and FPs identified different themes as triggers to initiate discussions about the EOL. The variation in triggers could lead to missed opportunities to engage in ACP in a timely manner.


Rising incidence of hip fracture in Gwangju City and Chonnam Province, Korea.
The purpose of study was to determine the incidence of hip fracture in 2001, to compare this with that of 1991, and to identify possible causes of change. Patients aged 50 yr or more living in Gwangju City and Chonnam Province, Korea, and who sustained a fracture of the hip during 2001 were investigated. Only patients who were admitted to hospitals for primary treatment of the first hip fracture were selected. There were 1,152 patients. A comparison of fracture incidences for 1991 and 2001 showed considerable increase during the 10-yr period. The total annual number of hip fractures rose from 247 in 1991 to 1,152 in 2001 and the fracture incidence also increased remarkably from 3.3 persons per 10,000 population in 1991 to 13.3 in 2001, representing a 4-fold increase over 10-yr. The reasons for this rising trend of hip fracture were not fully explained. However, an increase in the elderly population, an increase in osteoporosis, and an increase in injurious falls could partly account for the observed increase.


Chromosomal imbalances in the colorectal carcinomas with microsatellite instability.
Recent molecular genetic studies have revealed that two major types of genomic instabilities, chromosomal instability and microsatellite instability, exist in the colorectal carcinomas. To clarify the relationship between chromosomal abnormalities and mismatch repair gene defects in colorectal carcinomas, we performed a chromosomal analysis on 39 colorectal carcinomas with high-microsatellite instability (MSI-H) and compared the results obtained with those of 20 right-sided microsatellite-stable (MSS) colorectal carcinomas. Chromosomal imbalances (CIs) in MSS colorectal carcinomas were more frequent than in MSI-H colon carcinomas by comparative genomic hybridization analysis (70% versus 31%, P = 0.004). The CI patterns of MSI-H and MSS carcinomas were different. Frequent CIs in MSI-H colon carcinomas were gains of 4q (15%) and 8q (8%), and losses of 9q (21%), 1p (18%), and 11q (18%). In contrast, frequent CIs in right-sided MSS colon carcinomas were gains of 8q (50%), 13q (35%), and 20q (25%), and losses of 18q (55%), 15q (35%), and 17p (30%). We compared the mutation status of 45 target genes and CIs in our MSI-H tumors. Among these 45 target genes, mutation of hRAD50, a member of the DNA repair genes, and FLJ11383 were significantly related to MSI-H colorectal carcinomas with CIs (P = 0.01 and P = 0.02, respectively). Our findings indicate that unique CIs were present in a subset of MSI-H colorectal carcinomas and that these CIs are related to the mutation of several target genes, especially of hRAD50.


Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants.
Ten infants with classical maple syrup urine disease (MSUD) and two with variant MSUD had a total of 26 CT scans and 13 MR examinations of the brain during different stages of their disease. We found that inter- and intrapatient analyses of CT and MR findings at times ranging from 3 days to 7 months were typical enough to suggest the MSUD diagnosis. Imaging studies showed the natural course of the disease and, in a few cases, illustrated the effects of therapy. CT scans typically are negative during the first few days of life, then a marked, generalized, diffuse edema appears. In addition, a localized, more severe edema (the MSUD edema) is seen, which involves the deep cerebellar white matter, the dorsal part of the brainstem, the cerebral peduncles, and the dorsal limb of the internal capsule. Both the generalized and the MSUD edema subside during the second month of life, then may disappear totally or leave a well-defined, low-density zone around the lateral ventricles and small, low-attenuation lesions within the brainstem, respectively. With the disappearance of the edema, some loss of brain substance becomes obvious.


Capture-recapture method to determine the best design of a surveillance system. Application to a thyroid cancer registry.
The capture-recapture method is often confronted, when assessing completeness of surveys, to problems of dependence of data sources. The objective of this paper is to discuss the application of capture-recapture methods to choose the optimal combination of sources for a surveillance system. Our approach is based on: (1) using multiple sources, (2) assessing dependence between sources and between pools of dependent sources and other sources, (3) ruling out combinations that yield biased estimates, and (4) choosing the combinations of sources that have the best ratio between precision and applicability. We studied the independence for each pair of sources by computing the capture-recapture odds ratio. We characterized all combinations of sources by their sensitivity, coefficient of variation of the estimated number of cases, and level of resources needed to ascertain cases. Application of the approach is illustrated by data from a survey of thyroid cancer in New Caledonia, where five sources were used to estimate the incidence. The five sources provided 119 cases; the exhaustivity of sources and combinations of sources varied from 27.1 to 99.2%. Determination of dependence revealed ten dependencies out of 22 combinations. Coefficients of variation of the estimated number of cases varied from 0.83 to 27.79. The preferred combination included four sources and had a sensitivity of 97.5 and a coefficient of variation of 0.94. An assessment of dependence, based on simple criteria, can be used to choose the best combination of sources for a registry or a surveillance system.


Confocal microscopic visualization of MK-801-induced cytoplasmic vacuoles in vitro.
We examined neuroprotective and neurotoxic effects of the NMDA antagonist, MK-801, in primary cell cultures derived from embryonic mouse neocortex. Brief deprivation of oxygen and glucose, or direct application of N-methyl-D-aspartate (NMDA), resulted in acute neuronal swelling followed by neuronal death during the next day. This excitotoxic neuronal injury could be blocked by inclusion of a wide variety of NMDA antagonists in the cell culture medium. MK-801 attenuated neuronal death in the low micromolar range; 1 to 10 microM concentrations were sufficient to maximally reduce injury from NMDA toxicity, oxygen deprivation, or combined deprivation of oxygen and glucose. MK-801 alone caused no apparent toxicity at these concentrations in exposures of 24 to 48 hours. However, 24-hour exposure to 100 microM MK-801 resulted in appearance of cytoplasmic vacuoles, which could be visualized with immunofluorescence against the microtubule associated protein, MAP2, together with laser scanning confocal microscopy. Thus, at concentrations sufficient to block NMDA receptors, MK-801 is neuroprotective rather than neurotoxic for cortical neurons in vitro. This model system may provide a method to examine cellular mechanisms underlying the neurotoxicity of MK-801 at very high concentrations.


Evolutionary history of vegetative reproduction in Porpidia s.L. (Lichen-forming ascomycota).
The evolutionary history of gains and losses of vegetative reproductive propagules (soredia) in Porpidia s.l., a group of lichen-forming ascomycetes, was clarified using Bayesian Markov chain Monte Carlo (MCMC) approaches to monophyly tests and a combined MCMC and maximum likelihood approach to ancestral character state reconstructions. The MCMC framework provided confidence estimates for the reconstructions of relationships and ancestral character states, which formed the basis for tests of evolutionary hypotheses. Monophyly tests rejected all hypotheses that predicted any clustering of reproductive modes in extant taxa. In addition, a nearest-neighbor statistic could not reject the hypothesis that the vegetative reproductive mode is randomly distributed throughout the group. These results show that transitions between presence and absence of the vegetative reproductive mode within Porpidia s.l. occurred several times and independently of each other. Likelihood reconstructions of ancestral character states at selected nodes suggest that--contrary to previous thought--the ancestor to Porpidia s.l. already possessed the vegetative reproductive mode. Furthermore, transition rates are reconstructed asymmetrically with the vegetative reproductive mode being gained at a much lower rate than it is lost. A cautious note has to be added, because a simulation study showed that the ancestral character state reconstructions were highly dependent on taxon sampling. However, our central conclusions, particularly the higher rate of change from vegetative reproductive mode present to absent than vice versa within Porpidia s.l., were found to be broadly independent of taxon sampling.


Heart rate variability, the dynamic nature of the retinal microvasculature and cardiac stress: providing insight into the brain-retina-heart link: the SABPA study.
Decreased heart-rate-variability (HRV) indicates increased sympathetic nervous system (SNS) activity and modulation with a shift in the sympatho-vagal balance towards SNS predominance. Increased SNS activity may precede volume-loading hypertension, contribute to increases in cardiac troponin T (cTnT), endothelial dysfunction and small vessel disease. Therefore, we investigated the retinal vasculature, HRV during flicker-light-induced-provocation (FLIP) and systemic cTnT, a marker of cardiac stress, to provide further evidence in support of the brain-retina-heart link. Cross-sectional observations were obtained from a bi-ethnic cohort (N = 264), aged 23-68 years. Fasting serum samples for cTnT were obtained. Retinal vascular calibres were quantified from mydriatic eye fundus images and dynamic retinal vessel calibre responses were determined during FLIP. Time-and frequency domain parameters of HRV were calculated during FLIP for each participant. Africans had wider venules and attenuated time domain parameters during FLIP. In Africans, inverse associations emerged between arteriolar dilation and both cTnT and root-mean squared of the standard deviations of successive RR-intervals (rMSSD) (p = 0.030), and between arteriolar constriction and both low-frequency expressed in normalised units (LFnu) (p = 0.003) and high-frequency expressed in normalised units (p = 0.021). Wider venules inversely associated with standard deviation of the NN intervals (SDNN) as well as LFnu (p = 0.009) in Africans. An opposite profile was observed in Caucasians with both time-and frequency domain parameters of HRV in relation to retinal vessel structure and function. FLIP elicited increased SNS activity and modulation in this bi-ethnic cohort. In Africans, decreased HRV during FLIP accompanied arteriolar and venular responses and elevated systemic levels of cTnT, implying that the SNS exerted a significant effect on the smooth muscle tone of the retinal vasculature. Disrupted retinal autoregulation may imply general autonomic nervous system dysfunction; exemplifying central control by the brain on all systemic regulatory functions, across different vascular beds.


Frustrated phase transformations in supported, interdigitating lipid bilayers.
In free bilayers, the fluid to gel main phase transition of a monofluorinated phospholipid (F-DPPC) transforms a disordered fluid bilayer into a fully interdigitated monolayer consisting of ordered acyl tails. This transformation results in an increase in molecular area and decrease in bilayer thickness. We show that when confined in patches near a solid surface this reorganization proceeds under constraints of planar topography and total surface area. One consequence of these constraints is to limit the complete formation of the energetically favored, interdigitated gel phase. The noninterdigitated lipids experience enhanced lateral tension, due to the expansion of the growing interdigitated phase within the constant area. The corresponding rise in equilibrium transition temperatures produces supercooled lipids that vitrify when cooled further. Ultimately, this frustrated phase change reflects a coupling between dynamics and thermodynamics and gives rise to an unusual phase coexistence characterized by the presence of two qualitatively different gel phases.


Confidentiality Protections for Adolescents and Young Adults in the Health Care Billing and Insurance Claims Process.
The importance of protecting confidential health care for adolescents and young adults is well documented. State and federal confidentiality protections exist for both minors and young adults, although the laws vary among states, particularly for minors. However, such confidentiality is potentially violated by billing practices and in the processing of health insurance claims. To address this problem, policies and procedures should be established so that health care billing and insurance claims processes do not impede the ability of providers to deliver essential health care services on a confidential basis to adolescents and young adults covered as dependents on a family's health insurance plan.


Evaluation of resection margins in breast conservation therapy: the pathology perspective-past, present, and future.
Tumor surgical resection margin status is important for any malignant lesion. When this occurs in conjunction with efforts to preserve or conserve the afflicted organ, these margins become extremely important. With the demonstration of no difference in overall survival between mastectomy versus lumpectomy and radiation for breast carcinoma, there is a definite trend toward smaller resections combined with radiation, constituting "breast-conserving therapy." Tumor-free margins are therefore key to the success of this treatment protocol. We discuss the various aspects of margin status in this setting, from a pathology perspective, incorporating the past and current practices with a brief glimpse of emerging future techniques.


Phase-change switching in 2D via soft interactions.
We present a new type of phase-change behavior relevant for information storage applications, that can be observed in 2D systems with cluster-forming ability. The temperature-based control of the ordering in 2D particle systems depends on the existence of a crystal-to-glass transition. We perform molecular dynamics simulations of models with soft interactions, demonstrating that the crystalline and amorphous structures can be easily tuned by heat pulses. The physical mechanism responsible for this behavior is a self-assembled polydispersity, that depends on the cluster-forming ability of the interactions. Therefore, the range of real materials that can perform such a transition is very wide in nature, ranging from colloidal suspensions to vortex matter. The state of the art in soft matter experimental setups, controlling interactions, polydispersity and dimensionality, makes it a very fertile ground for practical applications.


On the estimation errors of KM and V from time-course experiments using the Michaelis-Menten equation.
The conditions under which the Michaelis-Menten equation accurately captures the steady-state kinetics of a simple enzyme-catalyzed reaction is contrasted with the conditions under which the same equation can be used to estimate parameters, KM and V, from progress curve data. Validity of the underlying assumptions leading to the Michaelis-Menten equation are shown to be necessary, but not sufficient to guarantee accurate estimation of KM and V. Detailed error analysis and numerical "experiments" show the required experimental conditions for the independent estimation of both KM and V from progress curves. A timescale, tQ, measuring the portion of the time course over which the progress curve exhibits substantial curvature provides a novel criterion for accurate estimation of KM and V from a progress curve experiment. It is found that, if the initial substrate concentration is of the same order of magnitude as KM, the estimated values of the KM and V will correspond to their true values calculated from the microscopic rate constants of the corresponding mass-action system, only so long as the initial enzyme concentration is less than KM.


An ORF2 protein-based ELISA for porcine circovirus type 2 antibodies in post-weaning multisystemic wasting syndrome.
Porcine circovirus type 2 (PCV2) plays a crucial role in the pathogenesis of post-weaning multisystemic wasting syndrome (PMWS) in swine. As PCV2 displays significant homology with PCV1 (a non-pathogenic virus) at the nucleotide and amino-acid level, a discriminative antigen is needed for specific serological diagnosis. The ORF2-encoded capsid protein from PCV2 was used to develop an indirect enzyme-linked immunosorbent assay (ELISA). GST-fused capsid protein from PCV2 and GST alone (both expressed in recombinant baculovirus-infected cells) were used as antigens for serodiagnosis. The specificity of the ELISA for detection of PCV2 antibodies was demonstrated in sera from pigs experimentally infected with PCV1, PCV2 and other swine viruses. The semi-quantitative nature of the test was evaluated versus an immunoperoxidase monolayer assay (IPMA). The ELISA was performed on 322 sera from pigs in eight Brittany herds and compared with IPMA. The sensitivity (98.2%) and specificity (94.5%) of this test were considered suitable for individual serological detection. High PCV2 seroprevalence was found in sows and pigs at the end of the growth phase (18-19 weeks) in all eight herds. The seroprevalence in piglets (11-17 weeks) was statistically correlated with clinical symptoms of PMWS (93% in affected versus 54%, in non-affected farms). A cohort study performed in PMWS-free farms showed that 57% of piglets exhibited active seroconversion after 13 weeks, indicating that PCV2 infection occurred earlier in PMWS-affected piglets.


Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients.
Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality. Prospective cohort study with a 4.5-year follow-up period. From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality. At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m(2). No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2-Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2-Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33-0.74; adjusted HR 0.62, 95% CI 0.42-0.939; CV events: Q2-Q5 versus Q1: crude HR 0.54, 95% CI 0.38-0.77; adjusted HR 0.68, 95% CI 0.48-0.97). Kaplan-Meier curves revealed similar data. Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors.


Interconnecting gold islands with DNA origami nanotubes.
Scaffolded DNA origami has recently emerged as a versatile, programmable method to fold DNA into arbitrarily shaped nanostructures that are spatially addressable, with sub-10-nm resolution. Toward functional DNA nanotechnology, one of the key challenges is to integrate the bottom-up self-assembly of DNA origami with the top-down lithographic methods used to generate surface patterning. In this report we demonstrate that fixed length DNA origami nanotubes, modified with multiple thiol groups near both ends, can be used to connect surface patterned gold islands (tens of nanometers in diameter) fabricated by electron beam lithography (EBL). Atomic force microscopic imaging verified that the DNA origami nanotubes can be efficiently aligned between gold islands with various interisland distances and relative locations. This development represents progress toward the goal of bridging bottom-up and top-down assembly approaches.


Effect of Amplitude and Number of Repetitions of the Perturbation on System Identification of Human Balance Control During Stance.
To unravel the underlying mechanisms of human balance control, system identification techniques are applied in combination with dedicated perturbations, like support surface translations. However, it remains unclear what the optimal amplitude and number of repetitions of the perturbation signal are. In this study we investigated the effect of the amplitude and number of repetitions on the identification of the neuromuscular controller (NMC). Healthy participants were asked to stand on a treadmill while small continuous support surface translations were applied in the form of a periodic multisine signal. The perturbation amplitude varied over seven conditions between 0.02 and 0.20 m peak-to-peak (ptp), where 6.5 repetitions of the multisine signal were applied for each amplitude, resulting in a trial length of 130 sec. For one of the conditions, 24 repetitions were recorded. The recorded external perturbation torque, body sway and ankle torque were used to calculate both the relative variability of the frequency response function (FRF) of the NMC, i.e., a measure for precision, depending on the noise-to-signal ratio (NSR) and the nonlinear distortions. Results showed that the perturbation amplitude should be minimally 0.05 m ptp, but higher perturbation amplitudes are preferred since they resulted in a higher precision, due to a lower noise-to-signal ratio (NSR). There is, however, no need to further increase the perturbation amplitude than 0.14 m ptp. Increasing the number of repetitions improves the precision, but the number of repetitions minimally required, depends on the perturbation amplitude and the preferred precision. Nonlinear contributions are low and, for the ankle torque, constant over perturbation amplitude.


Patterns of Waterpipe Tobacco Smoking Among U.S. Young Adults, 2013-2014.
Patterns of waterpipe smoking and associated other tobacco use were assessed among U.S. young adults (aged 18-24 years). A descriptive analysis of baseline data (2013-2014) from the Population Assessment of Tobacco and Health Study was conducted in 2016. The study included 9,119 young adults-44% ever and 11% past-30 day waterpipe smokers (12% of men and 9% of women were past-30 day smokers). Among past-30 day smokers, waterpipe smoking frequency was distributed as follows: 4% daily, 23% weekly, 36% monthly, and 37% less than monthly. The average session exceeded 30 minutes for 79% of respondents. In this age group, 29% were exclusive waterpipe smokers, 16% were dual (waterpipe/cigarette) smokers, 8% were dual (waterpipe/e-cigarette) users, 19% were waterpipe/cigarette/e-cigarette users, and 28% presented with other combinations of poly use. Waterpipe smoking is widespread among U.S. young adults. Although waterpipe patterns are predominantly intermittent, the average smoking session provides prolonged exposure. Waterpipe smoking among young adults is primarily characterized by the use of flavored tobacco, the café culture, and poly tobacco use. Rising trends in waterpipe smoking among U.S. youth warrant a strong regulatory response to prevent future waterpipe-related morbidity and mortality.


The passive permeability of the skin of anuran amphibia: a comparison of frogs (Rana pipiens) and toads (Bufo marinus).
1. Efflux of Na across dorsal skin, in vitro (bathed on both sides with Ringer solution), of frogs and toads were similar, but it was greater in ventral skin from the latter. 2. The efflux of Na declined, in both species, when the external surface of ventral, but not dorsal, skin was exposed to hyposmotic solutions with a low Na concentration. This change in Na permeability was influenced by the low osmotic concentration as well as the low Na concentration. 3. Efflux of Cl was similar in both the dorsal and ventral skin preparations (Ringer on both sides) from frogs and toads. 4. Chloride efflux declined in all skin preparations exposed on the external surface to dilute Ringer solution. Solute replacement with sucrose or choline or Na2SO4 showed that the decreased Cl efflux was principally due to the low Cl concentration, though Na may also contribute. This observation suggests the presence of Cl-/Cl- exchange diffusion mechanism. 5. Cutaneous urea permeability was less in toads than frogs and the dorsal and ventral skin was similar with respect to this solute in each species. 6. The presence of external hyposmotic solutions reduced the efflux, but not the influx, of urea across frog, but not toad, skin and it appeared that solvent 'drag' may contribute to this change. 7. Diffusion permeability to water was greater in frogs than toads and in the latter the ventral skin was more permeable than the dorsal. 8. The passive permeability of amphibian skin shows considerable interspecific and regional differences to various molecules which do not necessarily parallel each other. The control of passive cutaneous permeability appears to involve a variety of specific mechanisms, the distribution of which may have evolved during their adaptation to different environments.


The father's role during infancy. Factors that influence maternal expectations.
To describe factors that influence maternal expectations of the father's role during infancy. Cross-sectional survey. Postpartum obstetric ward of an inner-city teaching hospital. Mothers who were residents in the inner-city communities that surround the hospital and who were recently delivered of a newborn. Consecutive sampling from March to May 1992. Through structured maternal interviews, the father's expected role was measured in terms of accessibility, engagement in child care tasks, and decision-making responsibility. Influences included demographics, the mother's desire for the father's involvement, and her perceptions of his motivation, prenatal support, and ability to parent. Of 226 eligible mothers, 197 (87%) were interviewed. Expectations varied widely. Concerning accessibility, 48% and 18% of the mothers expected to see the father daily and less than weekly, respectively. Concerning engagement, 81% of the mothers expected some paternal involvement; the average mother assumed that the father would participate in one third of child care tasks. Concerning decision-making responsibility, 34% of the mothers expected to share all decisions; 30% expected to share none. In all areas, expectations were positively associated with the mother's desires, the strength of the parents' relationship, and the mother's perceptions of the father's motivation and ability to parent and the father's prenatal involvement (all, P < .001). Expected accessibility and engagement were greater for fathers who worked; expected engagement and decision-making responsibility were greater for fathers without children from other relationships (all, P < .03). The maternal desire for the father's participation, the strength of the parents' relationship, the mother's perception of the father as a parent, and the father's prenatal involvement are all consistently associated with the maternal expectations of the father's role. The demographic characteristics of either parent are not as strongly or consistently associated with the maternal expectations.


A mineral-rich red algae extract inhibits polyp formation and inflammation in the gastrointestinal tract of mice on a high-fat diet.
The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for chemoprevention against colon polyp formation. A total of 60 C57bl/6 mice were divided into 3 groups based on diet. One group received a low-fat, rodent chow diet (AIN76A). The second group received a high-fat "Western-style" diet (HFWD). The third group was fed the same HFWD with the mineral-rich extract included as a dietary supplement. Mice were maintained on the respective diets for 15 months. Autopsies were performed at the time of death or at the completion of the study. To summarize, the cumulative mortality rate was higher in mice on the HFWD during the 15-month period (55%) than in mice from the low-fat diet or the extract-supplemented high-fat diet groups (20% and 30%, respectively; P < .05 with respect to both). Autopsies revealed colon polyps in 20% of the animals on the HFWD and none in animals of the other 2 groups (P < .05). In addition to the grossly visible polyps, areas of hyperplasia in the colonic mucosa and inflammatory foci throughout the gastrointestinal tract were observed histologically in animals on the high-fat diet. Both were significantly reduced in animals on the low-fat diet and animals on the extract-supplemented HFWD.These data suggest that the mineral-rich algae extract may provide a novel approach to chemoprevention in the colon.


Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: a multicentre prospective cohort study.
To evaluate the association of genetic polymorphisms APOE, APOE G-219T promoter, microtubule associated protein(MAPT)/tau exon 6 Ser53Pro, MAPT/tau Hist47Tyr, IL-6572 G/C and IL-6RAsp358Ala with the risk of concussion in college athletes. A 23-centre prospective cohort study of 1056 college athletes with genotyping was completed between August 2003 and December 2012. All athletes completed baseline medical and concussion questionnaires, and post-concussion data were collected for athletes with a documented concussion. The study cohort consisted of 1056 athletes of mean±SD age 19.7±1.5 years, 89.3% male, 59.4% Caucasian, 35.0% African-American, 5.6% other race. The athletes participated in American football, soccer, basketball, softball, men's wrestling and club rugby. A total of 133 (12.1% prevalence) concussions occurred during an average surveillance of 3 years per athlete. We observed a significant positive association between IL-6R CC (p=0.001) and a negative association between APOE4 (p=0.03) and the risk of concussion. Unadjusted and adjusted logistic regression analysis showed a significant association between IL-6R CC and concussion (OR 3.48; 95% CI 1.58 to 7.65; p=0.002) and between the APOE4 allele and concussion (OR 0.61; 95% CI 0.38 to 0.96; p=0.04), which persisted after adjustment for confounders. IL-6R CC was associated with a three times greater concussion risk and APOE4 with a 40% lower risk.


The Short French Internet Addiction Test Adapted to Online Sexual Activities: Validation and Links With Online Sexual Preferences and Addiction Symptoms.
The goal of this study was to investigate the psychometric properties of a French version of the short Internet Addiction Test adapted to online sexual activities (s-IAT-sex). The French version of the s-IAT-sex was administered to a sample of 401 men. The participants also completed a questionnaire that screened for sexual addiction (PATHOS). The relationships of s-IAT-sex scores with time spent online for online sexual activities (OSAs) and the types of OSAs favored were also considered. Confirmatory analyses supported a two-factor model of s-IAT-sex, corresponding to the factorial structure found in earlier studies that used the short IAT. The first factor regroups loss of control and time management, whereas the second factor regroups craving and social problems. Internal consistency for each factor was evaluated with Cronbach's α coefficient, resulting in .87 for Factor 1, .76 for Factor 2, and .88 for the global scale. Concurrent validity was supported by relationships with symptoms of sexual addiction, types of OSAs practiced, and time spent online for OSAs. The prevalence of sexual addiction (measured by PATHOS) was 28.1% in the current sample of self-selected male OSA users. The French version of the s-IAT-sex presents good psychometric properties and constitutes a useful tool for researchers and practitioners.


Preliminary Validation of Japanese Version of the Parental Burnout Inventory and Its Relationship With Perfectionism.
Parenting is a precious experience and also a very hard task, which could result in parental burnout for some parents. The present study sought to validate a Japanese version of the Parental Burnout Inventory (PBI-J) by replicating and extending the pioneering work of Roskam et al. (2017). We conducted a web survey (N = 1200) to first validate the PBI-J and second to investigate the association between the PBI-J and perfectionism as a new interrelation. Similar to the prior study of Roskam et al. (2017), confirmatory factor analysis supported a model of three-factor structure of the PBI-J: emotional exhaustion, lack of personal accomplishment, and emotional distancing. In addition, we found low to moderate correlations of parental burnout with job burnout, parental stress, and depression. These findings provided initial evidence for validity of the PBI-J and suggested that parental burnout appeared to be different from job burnout. Our further evaluation of perfectionism confirmed such a difference between parental and job burnout by showing that parental perfectionism [i.e., combination of parental personal standards (PS) and parental concern over mistakes (CM)] has a unique contribution to parental burnout than does job perfectionism (i.e., combination of job PS and job CM). In addition, CM was positively correlated with burnout in both domains whereas the associations between PS and burnout were more complex. Finally, the proportion of parents experiencing burnout was estimated to lie somewhere between 4.2 and 17.3% in Japan. Overall, the present study confirmed preliminary validity of the PBI-J and found that parental perfectionism is one of the vulnerability factors in parental burnout.


Human skin physiology studied by particle probe microanalysis.
Particle probe methods (electron probe and proton probe X-ray microanalysis) have been applied to investigate the distribution of elements and water over the different layers of the epidermis. For major elements, electron probe X-ray microanalysis (XRMA) provides the advantage of superior spatial resolution, but for trace element analysis the more sensitive proton probe (particle induced X-ray emission, PIXE) analysis has to be used. On a dry weight basis, the concentration of S is rather constant across the epidermis, whereas the concentrations of P, K, Cl and Na show gradients with high levels in stratum germinativum (basale) and stratum spinosum but low levels in the stratum granulosum and stratum corneum. Essentially, Fe and Zn are confined to the basal region in normal skin. The concentration of Ca, however, increased steadily from the basal region to the stratum corneum. The probe technique allows quantitative analysis of stratum-specific changes in elemental content in a variety of pathological conditions, e.g., changes induced by nickel, detergents and other chemicals, or in psoriatic skin. Of particular interest are findings of increased Fe and Zn in non-involved psoriatic skin. Since the different layers of the skin have different elemental concentrations and react differently under pathological conditions, the probe techniques are far superior to bulk chemical analysis in elucidating physiological and pathological processes in the skin.


Ultra-Sensitive High-Resolution Profiling of Anti-SARS-CoV-2 Antibodies for Detecting Early Seroconversion in COVID-19 Patients.
The COVID-19 pandemic continues to infect millions of people worldwide. In order to curb its spread and reduce morbidity and mortality, it is essential to develop sensitive and quantitative methods that identify infected individuals and enable accurate population-wide screening of both past and present infection. Here we show that Single Molecule Array assays detect seroconversion in COVID-19 patients as soon as one day after symptom onset using less than a microliter of blood. This multiplexed assay format allows us to quantitate IgG, IgM and IgA immunoglobulins against four SARS-CoV-2 targets, thereby interrogating 12 antibody isotype-viral protein interactions to give a high resolution profile of the immune response. Using a cohort of samples collected prior to the outbreak as well as samples collected during the pandemic, we demonstrate a sensitivity of 86% and a specificity of 100% during the first week of infection, and 100% sensitivity and specificity thereafter. This assay should become the gold standard for COVID19 serological profiling and will be a valuable tool for answering important questions about the heterogeneity of clinical presentation seen in the ongoing pandemic.


Altered resting state in diabetic neuropathic pain.
The spontaneous component of neuropathic pain (NP) has not been explored sufficiently with neuroimaging techniques, given the difficulty to coax out the brain components that sustain background ongoing pain. Here, we address for the first time the correlates of this component in an fMRI study of a group of eight patients suffering from diabetic neuropathic pain and eight healthy control subjects. Specifically, we studied the functional connectivity that is associated with spontaneous neuropathic pain with spatial independent component analysis (sICA). Functional connectivity analyses revealed a cortical network consisting of two anti-correlated patterns: one includes the left fusiform gyrus, the left lingual gyrus, the left inferior temporal gyrus, the right inferior occipital gyrus, the dorsal anterior cingulate cortex bilaterally, the pre and postcentral gyrus bilaterally, in which its activity is correlated negatively with pain and positively with the controls; the other includes the left precuneus, dorsolateral prefrontal, frontopolar cortex (both bilaterally), right superior frontal gyrus, left inferior frontal gyrus, thalami, both insulae, inferior parietal lobuli, right mammillary body, and a small area in the left brainstem, in which its activity is correlated positively with pain and negatively with the controls. Furthermore, a power spectra analyses revealed group differences in the frequency bands wherein the sICA signal was decomposed: patients' spectra are shifted towards higher frequencies. In conclusion, we have characterized here for the first time a functional network of brain areas that mark the spontaneous component of NP. Pain is the result of aberrant default mode functional connectivity.


A performance improvement initiative for enhancing the care of patients with depression.
Depression is a common and potentially disabling condition, yet many patients remain undiagnosed, and many more fail to receive adequate treatment. To address this gap, clinicians must routinely evaluate patient care practices. The purpose of this study was to evaluate the effectiveness of a three-stage performance improvement (PI) continuing medical education (CME) initiative to strengthen evidence-based psychiatric practices for the screening and management of patients with depression. A total of 492 physician participants voluntarily registered to complete a three-stage initiative consisting of self-evaluation, improvement, and reevaluation. Participants were recruited through a series of faxes, e-mails, and direct-mail invitations. Approximately 20% (n=86) of the registrants completed the three-stage initiative. Completers provided chart data on 2,122 patients encountered before and 2,130 patients encountered after engaging in the PI CME activity. Large gains were made in the percentage of patients screened using standardized criteria to assess depression status, particularly the Patient Health Questionnaire-2 (PHQ-2) and the PHQ-9 (26% of 1,378 patients at Stage A vs.68% of 1,711 patients at Stage C; p<0.001). Physicians were also more likely to rescreen patients 4 to 8 weeks after initial screening (48% of 1,961 patients at Stage A vs. 75% of 2,028 patients at Stage C; p<0.001) and to assess patient adherence to antidepressants using standardized measures (10% of 1,909 patients at Stage A vs. 45% of 1,740 patients at Stage C; p<0.001). PI CME provides insight into and aids in improving evidence-based patient care in psychiatric practices.


Gradients and modulation of K(+) channels optimize temporal accuracy in networks of auditory neurons.
Accurate timing of action potentials is required for neurons in auditory brainstem nuclei to encode the frequency and phase of incoming sound stimuli. Many such neurons express "high threshold" Kv3-family channels that are required for firing at high rates (> -200 Hz). Kv3 channels are expressed in gradients along the medial-lateral tonotopic axis of the nuclei. Numerical simulations of auditory brainstem neurons were used to calculate the input-output relations of ensembles of 1-50 neurons, stimulated at rates between 100-1500 Hz. Individual neurons with different levels of potassium currents differ in their ability to follow specific rates of stimulation but all perform poorly when the stimulus rate is greater than the maximal firing rate of the neurons. The temporal accuracy of the combined synaptic output of an ensemble is, however, enhanced by the presence of gradients in Kv3 channel levels over that measured when neurons express uniform levels of channels. Surprisingly, at high rates of stimulation, temporal accuracy is also enhanced by the occurrence of random spontaneous activity, such as is normally observed in the absence of sound stimulation. For any pattern of stimulation, however, greatest accuracy is observed when, in the presence of spontaneous activity, the levels of potassium conductance in all of the neurons is adjusted to that found in the subset of neurons that respond better than their neighbors. This optimization of response by adjusting the K(+) conductance occurs for stimulus patterns containing either single and or multiple frequencies in the phase-locking range. The findings suggest that gradients of channel expression are required for normal auditory processing and that changes in levels of potassium currents across the nuclei, by mechanisms such as protein phosphorylation and rapid changes in channel synthesis, adapt the nuclei to the ongoing auditory environment.


Breast and cervical cancer screening: exploring perceptions and barriers with Hmong women and men in Oregon.
Hmong women are reported to have very low rates of breast and cervical cancer screening compared to other Asian and White women in the USA. Reasons for low cancer screening rates among this population are not well understood. This qualitative study (n=83) explored Hmong women and men's perceptions of breast and cervical cancer and cancer screening, women's experiences with breast and cervical cancer screening, and health care system barriers to screening. Hmong women and men perceived breast cancer to be more severe than other types of cancers. Participants believed that breast cancer is curable if detected early. Cervical cancer was not well understood and was of greater concern than breast cancer because of its location within the body and its consequences for reproduction. In general, few participants had personal experiences with breast and/or cervical cancer. Overall, women and men had positive things to say about screenings for breast and cervical cancer, expressing that screenings offered a 'proof of illness.' The majority of women did not report any concerns with the exams themselves, although some discussed embarrassment, pain, and discomfort. Barriers to screening included lack of health insurance, making co-payments, language, and issues related to scheduling appointments. Barriers differed for younger and older women. Results of this study provide new insight into perceptions, experiences, and barriers to breast and cervical cancer screening among Hmong women and men. These findings have implications for developing culturally appropriate interventions to increase breast and cervical cancer screening in this population.


Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans.
Functional imaging of the human brain is an increasingly important technique for clinical and cognitive neuroscience research, with functional MRI (fMRI) of the blood oxygen level-dependent (BOLD) response and electroencephalography or magnetoencephalography (MEG) recordings of neural oscillations being 2 of the most popular approaches. However, the neural and physiological mechanisms that generate these responses are only partially understood and sources of interparticipant variability in these measures are rarely investigated. Here, we test the hypothesis that the properties of these neuroimaging metrics are related to individual levels of cortical inhibition by combining magnetic resonance spectroscopy to quantify resting GABA concentration in the visual cortex, MEG to measure stimulus-induced visual gamma oscillations and fMRI to measure the BOLD response to a simple visual grating stimulus. Our results demonstrate that across individuals gamma oscillation frequency is positively correlated with resting GABA concentration in visual cortex (R = 0.68; P < 0.02), BOLD magnitude is inversely correlated with resting GABA (R = -0.64; P < 0.05) and that gamma oscillation frequency is strongly inversely correlated with the magnitude of the BOLD response (R = -0.88; P < 0.001). Our results are therefore supportive of recent theories suggesting that these functional neuroimaging metrics are dependent on the excitation/inhibition balance in an individual's cortex and have important implications for the interpretation of functional imaging results, particularly when making between-group comparisons in clinical research.


Incidental minimal atypical lobular hyperplasia on core needle biopsy: correlation with findings on follow-up excision.
Atypical lobular hyperplasia (ALH), often an incidental finding in breast core biopsies, is largely considered to be a risk factor for carcinoma rather than a direct precursor. However, management of ALH is controversial. We review our experience with incidental minimal ALH on core biopsy, and correlate with excision and follow-up results. We evaluated all cases of ALH on core biopsy from 1999 to 2009 from our institution, focusing on cases with < or =3 foci of ALH (minimal), paired excision, and no other lesion on the core biopsy that by itself would require excision. Cases with discordant clinical/radiologic impressions, suggesting that a suspicious lesion had been missed on biopsy, were excluded. Therefore, the excisions were performed because of the diagnosis of ALH. Of 56 cases with ALH on biopsy and paired excision, 42 showed minimal ALH. On excision, 26 had residual ALH and 13 were benign. Three cases had other atypical lesions: lobular carcinoma in situ (2 cases) and mild atypical ductal hyperplasia separate from the biopsy site (1 case). On follow-up, only 1 patient developed subsequent ALH in the same breast. No other ipsilateral lesions were later diagnosed (mean follow-up 3.2 y). No case with ALH on biopsy had a lesion on excision requiring further treatment, suggesting that these patients can be managed more conservatively. Furthermore, no patients were diagnosed with a higher grade lesion in the same breast on follow-up. We propose that, if there is close radiologic correlation and follow-up, minimal incidental ALH on core biopsy (< or =3 foci) does not require excision.